Abstract

The intestine-specific homeobox transcription factor ISX is an IL-6-inducible proto-oncogene implicated in the development of hepatocellular carcinoma (HCC), but its mechanistic contributions to this process are undefined. In this study, we provide evidence that ISX mediates a positive feedback loop integrating inflammation, tryptophan cataboism and immune suppression. We found that ISX mediated IL-6-induced expression of the tryptophan catabolic enzymes IDO1 and TDO2 in HCC cells, resulting in an ISX-dependent increase in the tryptophan catabolite kynurenine and its receptor aryl hydrocarbon receptor (AHR). Activation of this kynurenine/AHR signaling axis acted through a positive feedback mechanism to increase ISX expression and enhance cellular proliferation and tumorigenic potential. RNAi-mediated attenuation of ISX or AHR reversed these effects. In an IDO1-dependent manner, ectopic expression of ISX induced expression of genes encoding the critical immune modulators CD86 (B7-2) and PD-L1, through which ISX conferred a significant suppressive effect on the CD8+ T cell response. In HCC specimens, expression of IDO1, kynurenine, AHR and PD-L1 correlated negatively with survival. Overall, our results identified a feed-forward mechanism of immune suppression in HCC organized by ISX which involves kynurenine-AHR signaling and PD-L1, offering insights into immune escape by HCC which may improve its therapeutic management.